Hypoxia Inhibits DNA Repair to Promote Malignant Progression

DNA repair is essential to genomic integrity of the cell. Numerous studies have provided compelling evidence that hereditary defects in DNA repair are linked with predispositions to cancer, shedding light on the mechanism of DNA repair and its importance in cancer biology. The majority of human cancers however rarely undergo somatic mutations in DNA repair genes, yet they acquire genetic alterations as they progress. Little is known about the mechanism of genetic alteration during malignant progression. We and others have shown recently that hypoxia—oxygen deficiency—plays an important role in inhibiting DNA repair. Tumor hypoxia gives rise to the over-expression and activation of hypoxia-inducible factor 1α (HIF-1α), an oxygen-sensitive transcription factor commonly over-expressed in human cancers. Although HIF-1α is best known for its transcriptional up-regulation of a host of target genes responsible for tumor growth and survival, in this chapter we describe a novel mechanism by which HIF-1α inhibits DNA repair, thereby promoting genetic alterations and malignant progression.

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